Effects Of Sphingosine Kinase1Inhibitors In Combination With5-FU On Human Gastric Cancer MGC-803Cells And The Possible Mechanisms

BackgroundGastric cancer is currently the fourth most common cancer in the world andnewly diagnosed cancer cases in8%of gastric malignancy. Although the operationmethod, the treatment of chemotherapy and support improved in recent decades,overall survival was not significantly increased.Gastric cancer is the second leadingcause of cancer death in the word (738,000deaths, accounting for9.7%of total). Thepathogenesis of gastric cancer is not clear. Since in the early stages of gastric cancerhave no obvious symptoms, about65%of gastric cancer patients have local or distantmetastases at the time of diagnosis, so they lost the opportunities of surgery, makingtreatment difficult. The5-year survival rate of patients with metastatic or advancedgastric cancer is very low, only5%-15%. Chemotherapy is an important therapeuticmodality for gastric cancer besides surgical resection,although the success rate of thistreatment is limited because of chemoresistance. Looking for a new target orchemosensitizer in the clinical treatment of gastric cancer is urgently needed. ObjectivesTo investigate the effects of sphingosine kinase1(SphK1) inhibitor N,N-dimethylsphingosine (DMS) combined with5-fluorouracil (5-FU) on theproliferation and apoptosis of gastric cancer MGC-803cells and to explore thepossible mechanisms involved.MethodsMGC-803cells were cultured in vitro. The effects of DMS and5-FU on cellproliferation, apoptosis, and cell cycle distribution of MGC-803cells were detectedby MTT assay and flow cytometer (FCM), respectively. The expressions of SphK1,TS, DPD, NF-κB p65and bcl-2proteins were detected by Western blot.ResultsDifferent concentrations of DMS or5-FU alone or in combination couldobviously inhibit the proliferation of MGC-803cells in a dose-dependent andtime-dependent manners (P＜0.05). And the proliferation inhibition rate of MGC-803cells in the combination group was significantly higher than that in the single druggroups (P＜0.05). Treatment of MGC-803cells with DMS did not affect the cellcycle distribution (P＞0.05). As compared with the cells without drug treatment,DMS or5-FU alone could obviously increase the apoptosis rate of MGC-803cells (P＜0.05); the apoptosis rate in the combination group was significantly higher thanthat in the single-drug groups (P＜0.05). The expression levels of SphK1, NF-κB p65and bcl-2proteins were down-regulated with the treatment of DMS alone or incombination, whereas those of TS and DPD were not affected.ConclusionDMS can inhibit the proliferation and induce apoptosis of gastric cancerMGC-803cells in vitro. It shows a good synergetic effect in combination with5-FU,probably by down-regulating the expressions of SphK1, NF-κB p65and bcl-2 proteins.